Abuse-proofed dosage form

ABSTRACT

The invention relates to a dosage form that is thermoformed without discoloration and is safeguarded from abuse, comprising at least one synthetic or natural polymer having a breaking strength of at least 500 N in addition to one or more active substances that could be subject to abuse. The invention also relates to a corresponding method for producing said dosage form.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.16/032,467, filed Jul. 11, 2018, now allowed, which is a Continuation ofU.S. patent application Ser. No. 15/459,180 filed Mar. 15, 2017, nowU.S. Pat. No. 10,058,548, which is a Continuation of U.S. patentapplication Ser. No. 15/132,325 filed Apr. 19, 2016, now U.S. Pat. No.9,629,807, which is a continuation of U.S. patent application Ser. No.14/875,007, filed Oct. 5, 2015, now abandoned, which is a Continuationof U.S. patent application Ser. No. 14/138,372, filed Dec. 23, 2013, nowabandoned, which is a Continuation of Ser. No. 13/723,273, filed Dec.21, 2012, now abandoned, which is a Continuation of U.S. patentapplication Ser. No. 11/462,216, filed Aug. 3, 2006, now abandoned,which is a Continuation-in-Part-application of U.S. patent applicationSer. No. 11/349,544 filed on Feb. 6, 2006, now U.S. Pat. No. 8,075,872,a Continuation-in-Part-Application of U.S. patent application Ser. No.11/348,295, filed on Feb. 6, 2006, now abandoned, and aContinuation-in-Part-Application of U.S. patent application Ser. No.10/718,112 filed on Nov. 20, 2003, now U.S. Pat. No. 8,114,383, andclaims priority of German Patent Application No. 10 2005 005446.3 filedon Feb. 4, 2005 and German Patent Application No. 10 336 400.5 filed onAug. 6, 2003.

BACKGROUND OF THE INVENTION

The present invention relates to an abuse-proofed dosage formthermoformed by extrusion without discoloration and containing, inaddition to one or more active ingredients with abuse potential (A)optionally together with physiologically acceptable auxiliary substances(B), at least one synthetic or natural polymer (C) and optionally atleast one wax (D), wherein the dosage form exhibits a breaking strength(=resistance to crushing) of at least 500 N, and to a process for theproduction of the dosage form according to the invention.

Many pharmaceutical active ingredients, in addition to having excellentactivity in their appropriate application, also have abuse potential,i.e. they can be used by an abuser to bring about effects other thanthose intended. Opiates, for example, which are highly active incombating severe to very severe pain, are frequently used by abusers toinduce a state of narcosis or euphoria.

In order to make abuse possible, the corresponding dosage forms, such astablets or capsules are comminuted, for example ground in a mortar, bythe abuser, the active ingredient is extracted from the resultant powderusing a preferably aqueous liquid and the resultant solution, optionallyafter being filtered through cotton wool or cellulose wadding, isadministered parenterally, in intravenously. An additional phenomenon ofthis administration, in comparison with abusive oral administration, isa further accelerated increase in active ingredient levels giving theabuser the desired effect, namely the “kick” or “rush”. This kick isalso obtained if the powdered dosage form is administered nasally, i.e.is sniffed. Since controlled-release dosage forms containing activeingredients with abuse potential do not give rise to the kick desired bythe abuser when taken orally even in abusively high quantities, suchdosage forms are also comminuted and extracted in order to be abused.

U.S. Pat. No. 4,070,494 proposed adding a swellable agent to the dosageform in order to prevent abuse. When water is added to extract theactive ingredient, this agent swells and ensures that the filtrateseparated from the gel contains only a small quantity of activeingredient,

The multilayer tablet disclosed in WO 95/20947 is based on a similarapproach to preventing parenteral abuse, said tablet containing theactive ingredient with abuse potential and at least one gel former, eachin different layers.

WO 03/015531 A2 discloses another approach to preventing parenteralabuse. A dosage form containing an analgesic opioid and a dye as anaversive agent is described therein. The color released by tamperingwith the dosage form is intended to discourage the abuser from using thedosage form which has been tampered with.

Another known option for complicating abuse involves adding antagoniststo the active ingredients to the dosage form, for example naloxone ornaltexone in the case of opioids, or compounds which cause aphysiological defense response, such as for example ipecacuanha (ipecac)root.

However, since in most cases of abuse it is still necessary to pulverizethe dosage form comprising an active ingredient suitable for abuse, itis an object of the present invention to complicate or prevent thepulverization preceding abuse of the dosage form using the meansconventionally available to a potential abuser.

It is a further object to provide a dosage form for active ingredientswith potential for abuse which ensures the desired therapeutic effectwhen correctly administered, but from which the active ingredientscannot be converted into a form suitable for abuse simply bypulverization.

An additional object is to provide a dosage form with enhanced stabilitywhen maintained under adverse conditions.

Yet another object is to provide an extrusion process for themanufacture of dosage forms having enhanced abuse prevention andstability characteristics.

A further object is to provide a dosage form having a surface morphologydifferent from that of the core of the dosage form.

An additional object is to provide a dosage form having a non-uniformmorphology in general and in particular a dosage form having a layeredmorphology, in each case where the composition of the dosage formremains uniform.

SUMMARY OF THE INVENTION

These objects have been achieved by the provision of the abuse-proofeddosage form thermoformed by extrusion without discoloration according tothe invention which contains, in addition to one or more activeingredients with abuse potential (A), at least one synthetic or naturalpolymer (C) optionally at least one wax (D), and optionally at least onephysiologically acceptable auxiliary substance (B), wherein the dosageform exhibits a breaking strength of at least 500 N.

The breaking strength of at least 500 N (measured as stated in thespecification) means that pulverization of the dosage form isconsiderably more difficult using conventional means, so considerablycomplicating or preventing the subsequent abuse.

If comminution is inadequate, parenteral, in particular intravenous,administration cannot be performed safely or extraction of the activeingredient therefrom takes too long for the abuser or there is no “kick”when taken orally, as release is not instantaneous.

As used herein, comminution means pulverization of the dosage form withconventional means which are available to an abuser, such as, forexample, a mortar and pestle, a hammer, a mallet or other usual meansfor pulverization by application of force.

The dosage form according to the invention is thus suitable forpreventing parenteral, nasal and/or oral abuse of active ingredients,preferably of pharmaceutical active ingredients, with abuse potential.

The advantageous properties of the dosage form according to theinvention, in particular also its mechanical properties, may notautomatically be achieved by simply processing components (A), (C),optionally (B) and optionally (D) by means of conventional methods forthe preparation of dosage forms. In fact, usually suitable apparatusesmust be selected for the preparation and critical processing parametersmust be adjusted, particularly pressure/force, temperature and time.Dosage forms exhibiting the desired properties may be obtained only ifin the course of the preparation of the dosage form the components areexposed to a sufficient pressure at a sufficient temperature for asufficient period of time. Thus, although it may be possible to utilizeconventional apparatuses, the process protocols usually must be adaptedin order to meet the required criteria.

Unlike prior art methods which involve the extrusion of polymers inadmixture with pharmaceutically active substances but which fail toprovide the dosage forms with the beneficial characteristics accordingto the present invention because unsuitable extruder types are chosenand/or improper extrusion parameters are adjusted, it has now beendiscovered that the combination of specific extruder type coupled withherein specified extrusion process parameters provides dosage forms withthe enhanced properties disclosed herein.

For example, U.S. Pat. No. 6,488,963 relates to pharmaceuticalformulations comprising a hot-melt extrudable mixture of a therapeuticcompound and a high molecular weight poly(ethylene oxide). It isdisclosed that any commercially available extruder model equipped tohandle dry feed and having a solid conveying zone, one or multipleheating zones, and an extrusion die may be used. A single screw extruderis preferred and used in the examples. Besides hot-met extrusion, otherequivalent processes such as injection molding, hot dipping, meltcasting and compression molding are said to be useful. Thepharmaceutical formulations obtained by the extrusion process accordingto U.S. Pat. No. 6,488,963, however, fundamentally differ from thedosage forms according to the present invention. This becomes directlyevident from the further processing of the extrudate of Example 2 ofU.S. Pat. No. 6,488,963, which, upon exiting the die, may be chopped tothe desired length and then be ground to a powder. According to U.S.Pat. No. 6,488,963, such powders are preferred for oral, buccal, andsublingual administration.

In contrast to the grindable pharmaceutical formulations according to.U.S. Pat. No. 6,488,963, it is an essential feature of the dosage formsaccording to the present invention that they exhibit a breaking strengthof at least 500 N thereby preventing them from being ground to a powder.In the preparation of the dosage forms according to the invention, asuitable extruder type has to be chosen and the extrusion parametershave to be properly adjusted in order to achieve a breaking strength ofat least 500 N. In general, single screw extruders of the type disclosedin U.S. Pat. No. 6,488,963 are not suitable to produce the dosage formsaccording to the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic view of the extrudate of the composition.

FIGS. 2A and 2B show schematic views of the preferred arrangements ofthe tubular domain within the dosage form.

FIG. 3 shows the measurement of the breaking strength of a tablet.

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutical active ingredients with abuse potential are known to theperson skilled in the art, as are the quantities thereof to be used andprocesses for the production thereof, and may be present in the dosageform according to the invention as such, in the form of thecorresponding derivatives thereof, in particular esters or ethers, or ineach case in the form of corresponding physiologically acceptablecompounds, in particular in the form of the salts or solvates thereof,as racemates or stereoisomers. The dosage form according to theinvention is also suitable for the administration of two or morepharmaceutical active ingredients in one dosage form. The dosage formpreferably contains just one specific active ingredient.

The dosage form according to the invention is in particular suitable forpreventing abuse of a pharmaceutical active ingredient selected from thegroup consisting of opioids, tranquilizers, preferably benzodiazepines,barbiturates, stimulants and other narcotics.

The dosage form according to the invention is very particularly suitablefor preventing abuse of an opioid, tranquilizer or another narcoticselected from the group consisting ofN-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide (alfentanil), 5,5-diallylbarbituric acid (allobarbital),allylprodine, alpha-prodine,8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (alprazolam), 2-diethylaminopropiophenone(amfepramone), (±)-α-methyl-phenethylamine (amphetamine),2-(α-methylphenethylamino)-2-phenylacetonitrile(amphetaminil),5-ethyl-5-isopentylbarbituric acid (amobarbital),anileridine, apocodeine, 5,5-diethylbarbituric acid(barbital),benzylmorphine, bezitramide,7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2 (3H)-one (bromazepam),2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo-[4,3-a] [1,4]diazepine (brotizolam),17-cyclopropylmethyl-4,5a-epoxy-7α [(S)-1-hydroxy-1, 2, 2trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol(buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital),butorphanol,(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)dimethylcarbamate (camazepam), (1S, 2S)-2-amino-1-phenyl-1-propanol(cathine/D-norpseudoephedrine),7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine 4-oxide(chlordiazepoxide), 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (clobazam),5-(2-chloro-phenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one (clonazepam),clonitazene, 7-chloro-2, 3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid (clorazepate),5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one (clotiazepam),10-chloro-11β-(2-chlorophenyl)-2,3,7,11β-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6 (5H)-one (cloxazolam), (−)-methyl-[3β-benzoyloxy-2β(1αH, 5αH)-tropancarboxylate] (cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinan-6α-ol (codeine),5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclorphan,cyprenorphine,7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one(delorazepam), desomorphine, dextromoramide,(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate(dextropropoxyphen), dezocine, diampromide, diamorphine,7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (diazepam),4,5α-epoxy-3-methoxy-17-methyl-6α-morphinano 1 (dihydrocodeine),4,5α-epoxy-17-methyl-3,6α-morphinandiol (dihydromorphine), dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,(6αR, 10αR)-6, 6,9-trimethyl-3-pentyl-6α,7,8,10α-tetrahydro-6H-benzo[c]chromen-1-ol(dronabinol), eptazocine, 8-chloro-6-phenyl-4H-[1,2,4] triazolo [4,3-a][1,4] benzodiazepine (estazolam), ethoheptazine, ethylmethylthiambutene,ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate](ethyl loflazepate), 4, 5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol(ethylmorphine), etonitazene, 4, 5α,epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol(etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine(fencamfamine), 7-[2-(α-methylphenethylamino)ethyl]-theophylline)(fenethylline), 3-(α-methylphenethylamino)propionitrile (fenproporex),N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl),7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(fludiazepam),5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one(flunitrazepam),7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H-one(flurazepam),7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one(halazepam), 10-bromo-113-(2-fluorophenyl)-2, 3, 7, 11β-tetrahydro [1,3]oxazolyl [3,2-d] [1,4] benzodiazepin-6(5H)-one (haloxazolam), heroin, 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone),4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone (hydromorphone),hydroxypethidine, isomethadone, hydroxymethyl morphinane, 11-chloro-8,12β-dihydro-2, 8-dimethyl-12β-phenyl-4H-[1, 3]oxazino[3, 2-d] [1,4]benzodiazepine-4,7(6H)-dione (ketazolam),1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone (ketobemidone),(3S,6S)-6-dimethyl-amino-4,4-diphenylheptan-3-yl acetate(levacetylmethadol (LAAM)), (−)-6-dimethylamino-4,4-diphenol-3-heptanone(levomethadone), (−)-17-methyl-3-morphinanol (levorphanol),levophenacylmorphane, lofentanil,6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1, 2-a] [1,4]-benzodiazepin-1 (4H)-one (loprazolam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one(lorazepam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(lormetazepam), 5-(4-chlorophenyl)-2, 5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol (mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine (medazepam),N-(3-chloropropyl)-α-methylphenethylamine (mefenorex), meperidine,2-methyl-2-propyltrimethylene dicarbamate (meprobamate), meptazinol,metazocine, methylmorphine, N, α-dimethylphenethylamine(meth-amphetamine), (+)-6-dimethyl amino-4, 4-diphenyl-3-heptanone(methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone),methyl [2-phenyl-2-(2-piperidyl)acetate] (methylphenidate),5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital), 3,3-diethyl-5-methyl-2, 4-piperidinedione (methyprylon), metopon,8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam), 2-(benzhydrylsulfinyl)acetamide(modafinil), 4,5α-epoxy-17-methyl-7-morphinan-3, 6α-diol (morphine),myrophine, (±)-trans-3-(1,1-dimethylheptyl)-7, 8, 10, 10α-tetrahydro-1-hydroxy-6, 6-dimethyl-6H-dibenzo [-b, d) pyran-9(6αH)-one (nabilone), nalbuphine, nalorphine, narceine, nicomorphine,1-methyl-7-nitro-5-phenyl-1H-1, 4-benzodiazepin-2(3H)-one (nimetazepam),7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam),7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nordazepam),norlevorphanol, 6-dimethylamino-4, 4-diphenyl-3-hexanone (normethadone),normorphine, norpipanone, the exudation for the plants belonging to thespecies Papaver somniferum (opium), 7-chloro-3-hydroxy-5-phenyl-H-1,4-benzodiazepin-2(3H)-one (oxazepam), (cis-trans)-10-chloro-2, 3, 7, 1b-tetrahydro-2-methyl-11b-phenyloxazolo[3, 2-d][1,4]benzodiazepin-6-(5H)-one (oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone),oxymorphone, plants and parts of plants belonging to the species Papaversomniferum (including the subspecies setigerum), papaveretum,2-imino-5-phenyl-4-oxazolidinone (pernoline), 1, 2, 3, 4, 5,6-hexahydro-6, 11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol (pentazocine), 5-ethyl1-5-(1-methylbutyl)-barbituric acid (pentobarbital), ethyl(1-methyl-4-phenyl-4-piperidine carboxylate) (pethidine), phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, pholcodine,3-methyl-2-phenylmorpholine (phenmetrazine), 5-ethyl-5-phenylbarbituricacid (phenobarbital), α, α-dimethylphenethylamine (phentermine),7-chloro-5-phenyl-1-(2-propynyl)-1H-1, 4-benzodiazepin-2 (3H)-one(pinazepam) α-(2-piperidyl)benzhydryl alcohol (pipradrol) 1′-(3-cyano-3,3-diphenylpropyl) [1, 4′-bipiperidine]-4′-carboxamide (piritramide),7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1, 4-benzodiazepin-2(3H)-one(prazepam), profadol, proheptazine, promedol, properidine, propoxyphene,N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl(3-[4-methoxycarbonyl-4-(N-phenylpropanamido)-piperidino]propanoate)(remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secobutabarbital),5-allyl-5-(1-methylbutyl)-barbituric acid (secobarbital),N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}-propionanilide(sufentanil), 7-chloro-2-hydroxy-methy l-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (temazepam),7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1, 4-benzodiazepin-2 (3H)-one(tetrazepam), ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine (cisand trans)), tramadol, 8-chloro,-6-(2-chlorophenyl)-1-methyl-4H-[1, 2,4]triazolo [4, 3-a] [1, 4] benzodiazepine (triazolam),5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital), (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R, 2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R, 2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol, (1RS, 3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexan-1, 3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutyl-phenyl)-propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)-propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)-propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)-propionate,(RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester andcorresponding stereoisomeric compounds, the corresponding derivativesthereof in each case, in particular amides, esters or ethers, and thephysiologically acceptable compounds thereof in each case, in particularthe salts and solvates thereof, particularly preferably hydrochlorides.

In a preferred embodiment the dosage form according to the inventioncontains one active substance with abuse potential (A) or more activesubstance with abuse potentials (A) selected from the group consistingof1,1-(3-dimethylamino-3-phenylpentamethylen)-6-fluor-1,3,4,9-tetrahydropyrano[3,4-b]indole,in particular its hemicitrate;1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1, 3, 4,9-tetrahydropyrano[3,4-b]indole, in particular its citrate; and1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1, 3, 4,9-tetrahydropyrano[3, 4-b]-6-fluoro-indole, in particular itshemicitrate. These compounds are known, for example, from WO 2004/043967or WO 2005/066183. The disclosure of these references is expresslyincorporated herein and made a part of this present application,

The amount of the active substance with abuse potential (A), based onthe total amount of the dosage form, is preferably within the range from0.01 to 95 wt.-%, more preferably from 0.5 to 80 wt.-%, still morepreferably 1.0 to 70 wt.-%, most preferably 5.0 to 60 wt.-% and inparticular 10 to 50 wt.-%. In a preferred embodiment it is more than 20wt.-%.

The dosage form according to the invention is in particular suitable forpreventing abuse of an opioid active ingredient selected from the groupcomprising oxycodone, hydromorphone, morphine, tramadol and thephysiologically acceptable derivatives or compounds thereof, preferablythe salts and solvates thereof, preferably the hydrochlorides thereof.

The dosage form according to the invention is furthermore in particularsuitable for preventing abuse of an opioid active ingredient selectedfrom the group comprising(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,(1R, 2R)-3-(2-dimethylaminoethyl-cyclohexyl)-phenol, the physiologicallyacceptable salts thereof, preferably hydrochlorides, physiologicallyacceptable enantiomers, stereoisomers, diastereomers and racemates andthe physiologically acceptable derivatives thereof, preferably ethers,esters or amides.

These compounds and processes for the production thereof are describedin EP-A-693475 or EP-A-780369. The disclosure of these references isexpressly incorporated herein and made a part of this presentapplication.

In order to achieve the necessary breaking strength of the dosage formaccording to the invention, at least one synthetic or natural polymer(C) is used. The polymer (C) contributes to the breaking strength of thedosage form of at least 500 N, measured using the method disclosed inthe specification. At least one polymer selected from the groupcomprising polyalkylene oxides, preferably polymethylene oxide,polyethylene oxide, polypropylene oxide; polyethylene, PolyPropylene,polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymersthereof, and mixtures of at least two of the stated polymers ispreferably used for this purpose. High molecular weight thermoplasticpolyalkylene oxides are preferred. High molecular weight polyethyleneoxides with a molecular weight of at least 0.5 million, preferably of atleast 1 million up to 15 million, determined by rheologicalmeasurements, are particularly preferred. These polymers have aviscosity at 25° C. of 4500 to 17600 cP, measured on a 5 wt. % aqueoussolution using a model RVF Brookfield viscosimeter (spindle no.2/rotational speed 2 rpm), of 400 to 4000 cP, measured on a 2 wt. %aqueous solution using the stated viscosimeter (spindle no. 1 or3/rotational speed 10 rpm) or of 1650 to 10000 cP, measured on a 1 wt. %aqueous solution using the stated viscosimeter (spindle no. 2/rotationalspeed 2 rpm).

The polymers are preferably used in powder form. They may be soluble inwater.

In order to achieve the necessary breaking strength of the dosage formaccording to the invention, it is furthermore possible additionally touse at least one natural or synthetic wax (D). The wax (D) contributesto the breaking strength of the dosage form of at least 500 N, measuredusing the method disclosed in the specification, Waxes with a softeningpoint of at least 60° C. are preferred. Carnauba wax and beeswax are.particularly preferred. Carnauba wax is very particularly preferred.Carnauba wax is a natural wax which is obtained from the leaves of thecarnauba palm and has a softening point of at least 80° C. When the waxcomponent is additionally used, it is used together with at least onepolymer (C) in quantities such that the dosage form has a breakingstrength of at least 500 N.

In a preferred embodiment, the breaking strength of the dosage formamounts to at least 500 N, to at least 600 N, to at least 700 N, to atleast 800 N, to at least 900 N, to at least 1000 N or even to at least1100 N.

Component (C) is preferably used in an amount of 20 to 99.9 wt. %,particularly preferably of at least 30 wt. %, very particularlypreferably of at least 40 wt. %, relative to the total weight of thedosage form.

In increasingly preferred embodiments, the dosage form according to theinvention has a density of at least 0.80 or at least 0.85 g/cm³, atleast 0.90 or at least 0.95 g/cm³, at least 1.00, at least 1.05 or atleast 1.10 g/cm³, in the range from 0.80 to 1.35 g/cm³, and inparticular in the range from 0.95 to 1.25 g/cm³.

The dosage form according to the invention is characterized by acomparatively homogeneous distribution of density. Preferably, thedensities of two segments of the dosage form having a volume of 1.0 mm³each, deviate from one another by not more than +10%, or by not morethan +7.5%, or by not more than +5.0%, most preferably not more than+2.5%, and in particular not more than +1.0%.

The dosage form according to the invention is characterized by acomparatively. homogeneous distribution of the active substance withabuse potential (A). Preferably, the content of component (A) in twosegments of the dosage form having a volume of 1.0 mm³ each, deviatesfrom one another by not more than ±10%, more preferably not more thanmore than ±7.5%, still more preferably not more than ±5.0%, mostpreferably not more than ±2.5%, and in particular not more than ±1.0%.

Preferably, the total weight of the dosage form according to theinvention is within the range from 0.01 g to 1.5 g, more preferably 0.05g to 1.2 g, still more preferably 0.1 g to 1.0 g, most preferably 0.2 gto 0.9 g and in particular 0.25 g to 0.8 g.

Auxiliary substances (B) which may be used are those known auxiliarysubstances which are conventional for the formulation of solid dosageforms. These are preferably plasticizers, such as polyethylene glycol,auxiliary substances which influence active ingredient release,preferably hydrophobic or hydrophilic, preferably hydrophilic polymers,very particularly preferably hydroxypropylcellulose, and/orantioxidants. Suitable antioxidants are ascorbic acid,butylhydroxyanisole, butylhydroxytoluene, salts of ascorbic acid,monothioglycerol, phosphorous acid, vitamin C, vitamin E and thederivatives thereof, sodium bisulfite, particularly preferablybutylhydroxytoluene (BHT) or butylhydroxyanisole (BHA) andca-tocopherol.

The antioxidant is preferably used in quantities of 0.01 to 10 wt. %,preferably of 0.03 to 5 wt. %, relative to the total weight of thedosage form.

The dosage forms according to the invention are distinguished in that,due their hardness, they cannot be pulverized in conventionalcomminution means available to an abuser, such as a mortar and pestle.This virtually rules out oral or parenteral, in particular intravenousor nasal abuse. However, in order to prevent any possible abuse of thedosage form according to the invention, the dosage forms according tothe invention may, in a preferred embodiment, contain further agentswhich complicate or prevent abuse as auxiliary substances (B).

The abuse-proofed dosage form according to the invention, whichcomprises, apart from one or more active ingredients with abusepotential, at least one hardening polymer (C) and optionally at leastone wax (D), may accordingly also comprise at least one of the followingcomponents (a)-(e) as auxiliary substances (B):

at least one substance which irritates the nasal passages and/orpharynx,

at least one viscosity-increasing agent, which, with the assistance of anecessary minimum quantity of an aqueous liquid, forms a gel with theextract obtained from the dosage form, which gel preferably remainsvisually distinguishable when introduced into a further quantity of anaqueous liquid,

at least one antagonist for each of the active ingredients with abusepotential,

at least one emetic,at least one dye as an aversive agent,at least one bitter substance.

Components (a) to (f) are additionally each individually suitable forabuse-proofing the dosage form according to the invention. Accordingly,component (a) is preferably suitable for proofing the dosage formagainst nasal, oral and/or parenteral, preferably intravenous, abuse,component (b) is preferably suitable for proofing against parenteral,particularly preferably intravenous and/or nasal abuse, component (c) ispreferably suitable for proofing against nasal and/or parenteral,particularly preferably intravenous, abuse, component (d) is preferablysuitable for proofing against parenteral, particularly preferablyintravenous, and/or oral and/or nasal abuse, component (e) is suitableas a visual deterrent against oral or parenteral abuse and component (f)is suitable for proofing against oral or nasal abuse. Combined useaccording to the invention of at least one of the above-statedcomponents makes it possible still more effectively to prevent abuse ofdosage forms according to the invention.

In one embodiment, the dosage form according to the invention may alsocomprise two or more of components (a)-(f) in a combination, preferably(a), (b) and optionally (c) and/or (f) and/or (e) or (a), (b) andoptionally (d) and/or (f) and/or (e).

In another embodiment, the dosage form according to the invention maycomprise all of components (a)-(f).

If the dosage form according to the invention comprises component (a) tocounter abuse, substances which irritate the nasal passages and/orpharynx which may be considered according to the invention are anysubstances which, when administered via the nasal passages and/orpharynx, bring about a physical reaction which is either so unpleasantfor the abuser that he/she does not wish to or cannot continueadministration, for example burning, or physiologically counteractstaking of the corresponding active ingredient, for example due toincreased nasal secretion or sneezing. These substances whichconventionally irritate the nasal passages and/or pharynx may also bringabout a very unpleasant sensation or even unbearable pain whenadministered parenterally, in particular intravenously, such that theabuser does not wish to or cannot continue taking the substance.

Particularly suitable substances which irritate the nasal passagesand/or pharynx are those which cause burning, itching, an urge tosneeze, increased formation of secretions or a combination of at leasttwo of these stimuli. Appropriate substances and the quantities thereofwhich are conventionally to be used are known per se to the personskilled or may be identified by simple preliminary testing.

The substance which irritates the nasal passages and/or pharynx ofcomponent (a) is preferably based on one or more constituents or one ormore plant parts of at least one hot substance drug.

Corresponding hot substance drugs are known per se to the person skilledin the art and are described, for example, in “PharmazeutischeBiologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner,2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982,pages 82 et seq. The disclosure of these references is expresslyincorporated herein and made a part of this present application.

A dosage unit is taken to mean a separate or separable administrationunit, such as for example a tablet or a capsule.

One or more constituents of at least one hot substance drug selectedfrom the group consisting of Allii sativi bulbus (garlic), Asari rhizomacum herba (Asarum root and leaves), Calami rhizoma (calamus root),Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper),Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizome(Javanese turmeric root), Galangae rhizome (galangal root), Myristicaesemen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen(white mustard seed), Sinapis nigri semen (black mustard seed),Zedoariae rhizome (zedoary root) and Zingiberis rhizoma (ginger root),particularly preferably from the group consisting of Capsici fructus(capsicum), Capsici fructus acer (cayenne pepper) and Piperis nigrifructus (pepper) may preferably be added as component (a) to the dosageform according to the invention.

The constituents of the hot substance drugs preferably compriseo-methoxy(methyl)phenol compounds, acid amide compounds, mustard oils orsulfide compounds or compounds derived therefrom.

Particularly preferably, at least one constituent of the hot substancedrugs is selected from the group consisting of myristicin, elemicin,isoeugenol, α-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids,preferably capsaicin, capsaicin derivatives, such asN-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin,homocapsaicin, norcapsaicin and nomorcapsaicin, piperine, preferablytrans-piperine, glucosinolates, preferably based on non-volatile mustardoils, particularly preferably based on p-hydroxybenzyl mustard oil,methylmercapto mustard oil or methylsulfonyl mustard oil, and compoundsderived from these constituents.

The dosage form according to the invention may preferably contain theplant parts of the corresponding hot substance drugs in a quantity of0.01 to 30 wt. %, particularly preferably of 0.1 to 0.5 wt. %, in eachcase relative to the total weight of the dosage unit.

If one or more constituents of corresponding hot substance drugs areused, the quantity thereof in a dosage unit according to the inventionpreferably amounts to 0.001 to 0.005 wt. %, relative to the total weightof the dosage unit.

Another option for preventing abuse of the dosage form according to theinvention consists in adding at least one viscosity-increasing agent asa further abuse-preventing component (b) to the dosage form, which, withthe assistance of a necessary minimum quantity of an aqueous liquid,forms a gel with the extract obtained from the dosage form, which gel isvirtually impossible to administer safely and preferably remainsvisually distinguishable when introduced into a further quantity of anaqueous liquid.

For the purposes of the present invention, visually distinguishablemeans that the active ingredient-containing gel formed with theassistance of a necessary minimum quantity of aqueous liquid, whenintroduced, preferably with the assistance of a hypodermic needle, intoa further quantity of aqueous liquid at 37° C., remains substantiallyinsoluble and cohesive and cannot straightforwardly be dispersed in sucha manner that it can safely be administered parenterally, in particularintravenously. The material preferably remains visually distinguishablefor at least one minute, preferably for at least 10 minutes.

The increased viscosity of the extract makes it more difficult or evenimpossible for it to be passed through a needle or injected. If the gelremains visually distinguishable, this means that the gel obtained onintroduction into a further quantity of aqueous liquid, for example byinjection into blood, initially remains in the form of a largelycohesive thread, which, while it may indeed be broken up into smallerfragments, cannot be disoersed or even dissolved in such a manner thatit can safely be administered parenterally, in particular intravenously.In combination with at least one optionally present component (a) to(e), this additionally leads to unpleasant burning, vomiting, bad flavorand/or visual deterrence.

Intravenous administration of such a gel would most probably result inobstruction of blood vessels, associated with serious harm to the healthof the abuser.

In order to verify whether a viscosity-increasing agent is suitable ascomponent (b) for use in the dosage form according to the invention, theactive ingredient is mixed with the viscosity-increasing agent andsuspended in 10 ml of water at a temperature of 25° C. If this resultsin the formation of a gel which fulfils the above-stated conditions, thecorresponding viscosity-increasing agent is suitable for preventing oraverting abuse of the dosage forms according to the invention.

If component (b) is added to the dosage form according to the invention,one or more viscosity-increasing agents are used which are selected fromthe group comprising microcrystalline cellulose containingcarboxymethylcellulose sodium (e.g. Avicel® RC 591, FMC Corporation,Philadelphia, Pa., US), carboxymethylcellulose sodium (Blanose® HerculesInc., Wilmington, US; CMC-Na C300P®, Cesalpinia Food S.p.A., Milano, IT;Frimulsion BLC-5®, Cesalpinia Food S.p.A., Milano, IT; Tylose C300 P® SETylose GmbH & Co. KG, Wiesbaden, DE), polyacrylic acid (Carbopol® 980NF, Noveon IP Holdings Corp., Cleveland, Ohio, US, Carbopol® 981, NoveonIP Holdings Corp., Cleveland, Ohio, US), locust bean flour (Cesagum®LA-200, Cesalpinia Food S.p.A., Milano, IT; Cesagum® LID/150, CesalpiniaFood S.p.A., Milano, IT; Cesagum® LN-1, Cesalpinia Food S.p.A., Milano,IT), pectins, preferably from citrus fruits or apples (Cesapectin® HMMedium Rapid Set, Cesalpinia Food S.p.A., Milano, IT), waxy maize starch(C*Gel 04201®, Cerestar Deutschland GmbH, Krefeld, DE), sodium alginate(Frimulsion ALG (E401)®, Cesalpinia Food S.p.A., Milano, IT), guar flour(Frimulsion BM®, Cesalpinia Food S.p.A., Milano, IT; Polygum 26/1-75®,Polygal AG, Marstetten, CH), iota carrageen (Frimulsion D021®,Cesalpinia Food S.p.A., Milano, IT), karaya gum, gellan gum (KelcogelF®, Kelcogel LT100®, CP Kelco ApS, Lille Skensved, DK), galactomannan(Meyprogat 150®, Meyhall Chemical, Kreuzlingen, CH), tara bean flour(Polygum 43/1®, Polygal AG, Marstetten, CH), propylene glycol alginate.(Protanal-Ester SD-LB®, FCM Biopolymer AS, Drammen, NO), sodiumhyaluronate, tragacanth, tara gum (Vidogum SF 200® Unipektin AG, Zirich,CH), fermented polysaccharide welan gum (K1A96), xanthan gum (Xantural180®). Xanthans are particularly preferred. The names stated in bracketsare the trade names by which the materials are known commercially. Ingeneral, a quantity of 0.1 to 20 wt. %, particularly preferably of 0.1to 15 wt. % of the stated viscosity-increasing agent(s) is sufficient tofulfill the above-stated conditions.

The component (b) viscosity-increasing agents, where provided, arepreferably present in the dosage form according to the invention inquantities of 25 mg per dosage unit, i.e. per administration unit.

In a particularly preferred embodiment of the present invention, theviscosity-increasing agents used as component (b) are those which, onextraction from the dosage form with the necessary minimum quantity ofaqueous liquid, form a gel which encloses air bubbles. The resultantgels are distinguished by a turbid appearance, which provides thepotential abuser with an additional optical warning and discourageshim/her from administering the gel parenterally.

Component (C) may also optionally serves as an additionalviscosity-increasing agent which, with the assistance of a minimumnecessary quantity of an aqueous liquid, forms a gel.

It is also possible to formulate the viscosity increasing agent and theother constituents in the dosage form according to the invention in amutually spatially separated arrangement.

In order to discourage and prevent abuse, the dosage form according tothe invention may furthermore comprise component (c), namely one or moreantagonists for the active ingredient or active ingredients with abusepotential, wherein the antagonists are preferably spatially separatedfrom the remaining constituents of the invention dosage according to theform and, when correctly used, do not exert any effect.

Suitable antagonists for preventing abuse of the active ingredients areknown per se to the person skilled in the art and may be present in thedosage form according to the invention as such or in the form ofcorresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof.

If the active ingredient present in the dosage form is an opioid, theantagonist used is preferably an antagonist selected from the groupcomprising naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphineor naluphine, in each case optionally in the form of a correspondingphysiologically acceptable compound, in particular in the form of abase, a salt or solvate. The corresponding antagonists, where component(c) is provided, are preferably used in a quantity of ≥1 mg,particularly preferably in a quantity of 3 to 100 mg, very particularlypreferably in a quantity of 5 to 50 mg. per dosage form, i.e. peradministration unit.

If the dosage form according to the invention comprises a stimulant asactive ingredient, the antagonist is preferably a neuroleptic,preferably at least one compound selected from the group consisting ofhaloperidol, promethazine, fluphenazine, perphenazine, levomepromazine,thioridazine, perazine, chlorpromazine chlorprothixine, zuclopentixol,flupentixol, prothipendyl, zetepine, benperidol, pipamperone, melperoneand bromperidol.

The dosage form according to the invention preferably comprises theseantagonists in a conventional therapeutic dose known to the personskilled in the art, particularly preferably in a quantity of twice tofour times the conventional dose per administration unit.

If the combination to discourage and prevent abuse of the dosage formaccording to the invention comprises component (d), it may comprise atleast one emetic, which is preferably present in a spatially separatedarrangement from the other components of the dosage form according tothe invention and, when correctly used, is intended not to exert itseffect in the body.

Suitable emetics for preventing abuse of an active ingredient are knownper se to the person skilled in the art and may be present in the dosageform according to the invention as such or in the form of correspondingderivatives, in particular esters or ethers, or in each case in the formof corresponding physiologically acceptable compounds, in particular inthe form of the salts or solvates thereof.

An emetic based on one or more constituents of ipecacuanha (ipecac)root, preferably based on the constituent emetine may preferably beconsidered in the dosage form according to the invention, as are, forexample, described in “Pharmazeutische Biologie—Drogen und ihreInhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition,Gustav Fischer Verlag, Stuttgart, New York, 1982. The disclosure ofthese references is expressly incorporated herein and made a part ofthis present application.

The dosage form according to the invention may preferably comprise theemetic emetine as component (d), preferably in a quantity of ≥3 mg,particularly preferably of ≥10 mg and very particularly preferably in aquantity of ≥20 mg per dosage form, i.e. administration unit.

Apomorphine may likewise preferably be used as an emetic in theabuse-proofing according to the invention, preferably in a quantity ofpreferably ≥3 mg, particularly preferably of ≥5 mg and very particularlypreferably of ≥7 mg. per administration unit.

If the dosage form according to the invention contains component (e) asa further abuse-preventing auxiliary substance, the use of a such a dyebrings about an intense coloration of a corresponding aqueous solution,in particular when the attempt is made to extract the active ingredientfor parenteral, preferably intravenous administration, which colorationmay act as a deterrent to the potential abuser. Oral abuse, whichconventionally begins by means of aqueous extraction of the activeingredient, may also be prevented by this coloration. Suitable dyes andthe quantities required for the necessary deterrence may be found in WO03/015531. The disclosure of this reference is expressly incorporatedherein and made a part of this present application.

If the dosage form according to the invention contains component (f) asa further abuse-preventing auxiliary substance, this addition of atleast one bitter substance and the consequent impairment of the flavorof the dosage form additionally prevents oral and/or nasal abuse.

Suitable bitter substances and the quantities effective for use may befound in US-2003/0064099 A1. The disclosure of this reference isexpressly incorporated herein and made a part of this presentapplication. Suitable bitter substances are preferably aromatic oils,preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol,fruit aroma substances, preferably aroma substances from lemons,oranges, limes, grapefruit or mixtures thereof, and/or denatoniumbenzoate (Bitrex®). Denatonium benzoate is particularly preferred.

The solid dosage form according to the invention is suitable to be takenorally, vaginally or rectally, preferably orally. The dosage form ispreferably not in film form.

The dosage form according to the invention may assume multiparticulateform, preferably in the form of microtablets, microcapsules,micropellets, granules, spheroids, beads or pellets, optionally packagedin capsules or pressed into tablets, preferably for oral administration.The multiparticulate forms preferably have a size or size distributionin the range from 0.1 to 3 mm, particularly preferably in the range from0.5 to 2 mm. Depending on the desired dosage form, conventionalauxiliary substances (B) are optionally also used for the formulation ofthe dosage form.

The solid, abuse-proofed dosage form according to the invention ispreferably produced by thermoforming with the assistance of an extruderwithout any observable consequent discoloration of the extrudates.

In order to investigate the extent of discoloration due to thisthermoforming, the color of the mixture of starting components of whichthe dosage form consists is first determined without addition of acolor-imparting component, such as for example a coloring pigment or anintrinsically colored component (for example α-tocopherol). Thiscomposition is then thermoformed according to the invention, wherein allprocess steps, including cooling of the extrudate, are preferablyperformed under an inert gas atmosphere. By way of comparison, the samecomposition is produced by. the same process, but without an inert gasatmosphere. The color of the dosage form produced according to theinvention from the starting composition and of the dosage form producedby way of comparison is determined. The determination is performed withthe assistance of “Munsell Book of Color” from Munsell Color CompanyBaltimore, Md., USA, 1966 edition. If the color of the dosage formthermoformed according to the invention has a color with identificationno. N 9.5, but at most a color with the identification no. 5Y 9/1,thermoforming is classed as being “without discoloration”. If the dosageform has a color with the identification no. 5Y 9/2 or greater, asdetermined according to the Munsell Book of Color, the thermoforming isclassed as being “with discoloration”.

Surprisingly, the dosage forms according to the invention exhibit nodiscoloration classed in accordance with the above classification, ifthe entire production process is performed under an inert gasatmosphere, preferably under a nitrogen atmosphere with the assistanceof an extruder for thermoforming.

In one embodiment of the present invention the abuse-proofed dosageforms are produced by a process comprising

mixing components (A), the optionally present component (B), (C) and theoptionally present component (D) and co-mixing the optionally presentcomponents a) to f) or, if necessary, separately mixing with theaddition of Component (C) and optionally (D),

heating the resultant mixture or the resultant mixtures in the extruderat least up to the softening point of component (C) and extruding themixture through the outlet orifice of the extruder by application offorce,

singulating and forming the still plastic extrudate into the dosage formor

cooling and forMing the extrudate into the dosage form,

wherein process steps II) and III) and optionally process steps I) andIV) are optionally performed under an inert gas atmosphere, preferably anitrogen atmosphere.

Mixing of the components according to process step I) may also proceedin the extruder.

Mixing of components (A), optionally (B), (C) and optionally (D) and ofthe optionally present further components (a)-(f) and optionallycomponents (C) and the optionally present component (D) may alsooptionally proceed in a mixer known to the person skilled in the art.The mixer may, for example, be a roll mixer, shaking mixer, shear mixeror compulsory mixer.

Before blending with the remaining components, component (C) and theoptionally present component (D) is preferably provided according to theinvention with an antioxidant. This may proceed by mixing the twocomponents, (C) and the antioxidant, preferably by dissolving orsuspending the antioxidant in a highly volatile solvent andhomogeneously mixing this solution or suspension with component (C) andthe optionally present component (D) and removing the solvent by drying,preferably under an inert gas atmosphere. Alternatively, aphysiologically acceptable auxiliary substance (B) or a wax (D) mayserve as the solvent, preferably at elevated temperature. For example,when polyethylene glycol is used as a plasticizer, it may be molten orliquefied at moderately elevated temperature and the antioxidant may bedissolved therein. Under these circumstances the highly volatile solventcan be omitted.

The dosage forms according to the invention which contain subunits withfurther auxiliary substances which prevent or complicate abuse may beproduced by coextruding or separately extruding the mixtures accordingto step I).

In any event, the, preferably molten, mixture or mixtures which has/havebeen heated in the extruder at least up to the softening point ofcomponent (C) is/are extruded from the extruder through a die with atleast one bore.

The process according to the invention is preferably performed usingconventional screw extruders, particularly preferablytwin-screw-extruders,

The extruder preferably comprises at least two temperature zones, withheating of the mixture at least up to the softening point of component(C) proceeding in the first zone, which is downstream from a feed zoneand optionally mixing zone, The throughput of the mixture is preferablyfrom 2.0 kg to 8.0 kg/hour.

After heating at least up to the softening point of component (C), themolten mixture is conveyed with the assistance of the screws, furtherhomogenized, compressed or compacted such that, immediately beforeemerging from the extruder die, it exhibits a minimum pressure of 5 bar,preferably of at least 10 bar, and is extruded through the die as anextruded strand or strands, depending on the number of bores which thedie comprises. The die geometry or the geometry of the bores is freelyselectable. The die or the bores may accordingly exhibit a round, oblongor oval cross-section, wherein the round cross-section preferably has adiameter of 0.1 mm to 15 mm and the oblong cross-section preferably hasa maximum lengthwise extension of 21 mm and a crosswise extension of 10mm. Preferably, the die or the bores have a round cross-section. Thecasing of the extruder used according to the invention may be heated orcooled. The corresponding temperature control, i.e. heating or cooling,is so arranged that the mixture to be extruded exhibits at least anaverage temperature (product temperature) corresponding to the softeningtemperature of component (C) and does not rise above a temperature atwhich the active substance with abuse potential which is to be processedmay be damaged. Preferably, the temperature of the mixture to beextruded is adjusted to below 180° C., preferably below 150° C., but atleast to the softening temperature of component (C).

In general, the following parameters are critical in extrusion processesand have the consequences. described;

1. Throughput (Kg Per Hour)

If the throughput is too low the extruder is not correctly filled andthe material is stressed thereby affecting the viscosity and the releaseprofile of the final product; if the throughput is too high the load ofthe extruder is higher than 100% and the extruder shuts downautomatically; and if the throughput is tolerable but close to the upperlimit significant expansion of the extruded strand occurs (also known as“die swelling”).

2. Screw Geometry

A minimum number of kneading elements is required in order to obtain ahomogeneous mixture; if the number is too high, the material is stressedthereby affecting the viscosity and the release profile of the finalproduct. The number and lead of the conveying elements influences thehomogeneity of the mixture and its residence time in the extruder andcontrols the increase of the pressure in front of the die. Mixingelements improve the homogeneity of the mixture; and eccentric screwheads allow for a continuous discharge of the extrudate without densityvariations.

3. Die and Merge Element Geometry

The geometry of the element which merges the extrusion strands in frontof the die, and geometry of the die itself, the residence time in saidelement, and the ratio length of the die to diameter of the dieinfluence the compression of the material thereby affecting the meltpressure. The die pressure depends on revolution, throughput and melttemperature and affects the viscosity and the release profile of thefinal product.

4. Temperature (Melt Zones)

The feeding cylinder should not be heated to prevent the startingmaterial from melting in the feeder and causing an accumulation. Thenumber of cylinders is variable, the longer the extruder the longer theresidence time. The temperature of the cylinders (except feedingcylinder) destroys the material if it is too high: if too low thematerial does not sufficiently melt thereby resulting in aninhomogeneous mixture and degradation. The die temperature, ifseparately set too low, causes the “extrusion skin” to not properly formthereby making further processing of the extrudate difficult.

5. Revolution of the Extruder

If the extruder revolution speed is too high the material is stressedthereby affecting the viscosity and the release profile of the finalproduct. If the extruder revolution speed is too low the load of theextruder is higher than 100% and the extruder shuts down automatically;and inter alia the residence time depends on the revolution.

6. Arrangement of Cylinders

The position of feeding cylinder and length of the extruder areimportant. The degassing should be located close to the feeder in orderto avoid air pockets in the product; and if one of the components isthermo-labile it may be separately fed into one of the rear cylinders.

7. Temperature of the Water Cooling

Cooling of the engine and control of the temperature of the extrusioncylinders are important parameters.

The process according to the invention requires the use of suitableextruders, preferably screw extruders. Screw extruders which areequipped with two screws (twin-screw-extruders) are particularlypreferred. Single-screw extruders are preferably excluded.

The extrusion is preferably performed so that the expansion of thestrand due to extrusion is not more than 50%, i.e. that when using a diewith a bore having a diameter of e.g. 6 mm, the extruded strand shouldhave a diameter of not more than 9 mm. More preferably, the expansion ofthe strand is not more than 40%, still more preferably not more than35%, most preferably not more than 30% and in particular not more than25%. It has been surprisingly found that if the extruded material in theextruder is exposed to a mechanical stress exceeding a certain limit, asignificant expansion of the strand occurs thereby resulting inundesirable irregularities most preferably not more than 30% and inparticular not more than 25%. It has been surprisingly found that if theextruded material in the extruder is exposed to a mechanical stressexceeding a certain limit, a significant expansion of the strand occursthereby resulting in undesirable irregularities of the properties of theextruded strand, particularly its mechanical properties.

For example, extrusion may be performed by means of atwin-screw-extruder type Micro 27 GL 40 D (Leistritz, Niirnberg,Germany), screw diameter 18 mm. Screws having eccentric ends may beused. A heatable die with a round bore having a diameter of 8 mm may beused. The entire extrusion process may be performed under nitrogenatmosphere. The extrusion parameters may be adjusted e.g. to thefollowing values: rotational speed of the screws: 100 Upm; deliveryrate: 4 kg/h; product temperature: 125° C.; and jacket temperature: 120°C.

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are preferablysingulated. This singulation may preferably be performed by cutting upthe extrudates by means of revolving or rotating knives, water jetcutters, wires, blades or with the assistance of laser cutters.

An inert gas atmosphere is not necessary for intermediate or finalstorage of the optionally singulated extrudate or the final shape of thedosage form according to the invention.

The singulated extrudate may be pelletized with conventional methods orbe press-molded into tablets in order to impart the final shape to thedosage form. It is, however, also possible not to singulate the extrudedstrands and, with the assistance of contrarotating calender rollscomprising opposing recesses in their outer sleeve, to form them intothe final shape, preferably a tablet, and to singulate these byconventional methods.

Should the optionally singulated extrudate not immediately be formedinto the final shape, but instead cooled for storage, after the periodof storage an inert gas atmosphere, preferably a nitrogen atmosphere,may optionally be provided and may be maintained during heating of thestored extrudate up until plasticization and definitive shaping to yieldthe dosage form.

The application of force in the extruder onto the at least plasticizedmixture is adjusted by controlling the rotational speed of the conveyingdevice in the extruder and the geometry thereof and by dimensioning theoutlet orifice in such a manner that the pressure necessary forextruding the plasticized mixture is built up in the extruder,preferably immediately prior to extrusion. The extrusion parameterswhich, for each particular composition, are necessary to give rise to adosage form with a breaking strength of at least 500 N, may beestablished by simple preliminary testing.

The process according to the invention involves the extrusion of acomposition comprising components (A), (C), optionally (B) andoptionally (D). Preferably, extrusion is performed by means oftwin-screw-extruders.

It has been surprisingly found that extrudates exhibiting anadvantageous morphology are obtainable by means of twin-screw-extruders.It has been found that under suitable conditions the extrudate issurrounded by a shell which may be denoted as “extrusion skin”. Saidextrusion skin can be regarded as a collar-like or tubular structureforming a circumferential section of the extrudate about itslongitudinal extrusion axis so that the outer surface of saidcollar-like or tubular structure forms the closed shell of theextrudate. Usually, only the front faces of the extrudate are notcovered by said extrusion skin.

The extrusion skin surrounds the core of the extrudate in a collar-likeor tubular arrangement and preferably is connected therewith in aseamless manner. The extrusion skin differs from said core in itsmorphology. Usually, the extrusion skin is visible with the naked eye inthe cross-section of the extrudate, optionally by means of a microscope,since due to the different morphology of the material forming theextrusion skin and the material forming the core, the optical propertiesdiffer as well. It seems that during extrusion the material forming theextrusion skin is exposed to mechanical and thermal conditions differingfrom the conditions the core of the extrudate is exposed to. Inconsequence, a heterogeneous morphology of the extruded strand isobtained, which e.g. assumes radial symmetry when an extrusion diehaving circular shape is used. The material forming the extrusion skinand the material forming the core are usually distinguished by theirmorphology, preferably, however, not by their composition, particularlynot by the relative content of components (A), (C), optionally (B) andoptionally (D).

Usually the extrusion skin covers the entire shell of the extrudate likea one-piece collar, independently of what geometry has been chosen forthe extrusion die. Therefore, the extrudate may assume circular,elliptic or other cross-sections.

The extrusion skin is preferably characterized by a. unitary thickness.Preferably, the thickness of the extrusion skin is within the range from0.1 to 4.0 mm, more preferably 0.15 to 3.5 mm, still more preferably 0.2to 3.0 mm, most preferably 0.2 to 2.5 mm and in particular 0.2 to 2.0mm. In a preferred embodiment the thickness of the extrusion skin in thesum over both opposing sides amounts to 0.5 to 50%, more preferably 1.0to 40%, still more preferably 1.5 to 35%, most preferably 2.0 to 30% andin particular 2.5. to 25% of the diameter of the extrudate.

FIG. 1 shows a schematic view of extrudate (71) having a collar-likeextrusion skin (72) entirely surrounding the core (73) about thelongitudinal extrusion axis (74). The outer surface of extrusion skin(72) forms the shell (75) of the extrudate (71).

It has been surprisingly found that extrudates having an extrusion skinexhibit beneficial mechanical properties. They are particularly suitableas intermediates in the production of the dosage forms according to theinvention, because they may be advantageously processed, in particularby singulating and/or forming.

When the dosage forms according to the invention are prepared by meansof extrusion processes which lead to intermediates having an extrusionskin as described above, the dosage forms obtained therefrom arepreferably also characterized by a particular morphology.

In a preferred embodiment those regions, which have formed the extrusionskin in the extruded intermediate, are still visible with the naked eye,optionally by means of a microscope, in the cross-section of the dosageform. This is because usually by further processing the extrudate,particularly by singulating and/or shaping, the different nature andthereby also the different optical properties of the material formingthe extrusion skin and the material forming the core are maintained. Inthe following, that domain of the dosage forms which has emerged fromthe extrusion skin in the course of further processing the extrudedintermediate, will be denoted as “tubular domain”.

Preferably, the dosage form according to the invention comprises atubular domain and a core located therein. Preferably, the tubulardomain is connected with the core in a seamless manner. Preferably thetubular domain as well as the core have substantially the same chemicalcomposition, i.e. substantially the same relative content of components(A), (C), optionally (B) and optionally (D). The material forming thetubular domain has a morphology differing from the material forming thecore. Usually, this different morphology is also expressed in terms ofdifferent optical oroperties, so that the tubular domain and the coreare visible with the naked eye in the cross-section of the dosage form.

In case that the dosage form has been coated, e,g. by a film coating,the tubular domain is located between the film coating and the core.

Since the dosage form according to the invention may be obtained indifferent ways from the extrudate containing the extrusion skin(intermediate), the tubular domain may take different arrangements andextensions within the dosage form according to the invention. Allarrangements have in common, however, that the tubular domain partiallycovers the surface of the core, but usually not its entire surface.Preferably, two opposing surfaces of the core are not, or at least notfully covered by the tubular domain. In other words, preferably thetubular domain has two openings/blanks on opposing sides.

The thickness of the tubular domain may be uniform. It is also possible,however, that in the course of the processing, i.e. due to thesubsequent shaping (e.g. press-forming) of the extrudate, varioussections of the extrusion skin are expanded or compressed differentlythereby leading to a variation of the thickness of the tubular domainwithin the dosage form.

Preferably the thickness of the tubular domain is within the range from0.1 to 4.0 mm, more preferably 0.15 to 3.5 mm, still more preferably 0.2to 3.0 mm, most preferably 0.2 to 2.5 mm and in particular 0.2 to 2.0mm.

FIGS. 2A and 2B show schematic views of preferred arrangements of thetubular domain within the dosage form according to the invention. Thedosage forms (81) contain a tubular domain (82) partially surroundingthe core (83). The opposing surfaces (84a) and (84b) of the core (83),however, are not covered by the tubular domain (82).

The process for the preparation of the dosage form according to theinvention is preferably performed continuously. Preferably, the processinvolves the extrusion of a homogeneous mixture of components (A), (C),optionally (B) and optionally (D). It is particularly advantageous ifthe obtained intermediate, e.g. the strand obtained by extrusion,exhibits uniform properties. Particularly desirable are uniform density,uniform distribution of the active substance, uniform mechanicalproperties, uniform porosity, uniform appearance of the surface, etc.Only under these circumstances the uniformity of the pharmacologicalproperties, such as the stability of the release profile, may be ensuredand the amount of rejects can be kept low.

Preferably, the process according to the present invention may beperformed with less than 25% rejects, more preferably less than 20%,most preferably less than 15% and in particular less than 10% rejects,wherein the criteria for rejection are the FDA standards regarding theintervariability of the content of component (A), its release profileand/or the density of the dosage form when comparing two dosage forms,preferably taken from the same batch.

It has been surprisingly found that the above properties may be obtainedby means of twin-screw-extruders.

The process according to the invention preferably involves the extrusionof a mixture of components (A), (C), optionally (B) and optionally (D),preferably by means of a twin-screw-extruder. After extrusion theextrudate is preferably singulated, shaped and optionally coated inorder to obtain the final dosage form.

In a preferred embodiment of the process according to the invention,shaping is performed in the plasticized state of the mixture ofcomponents (A), (C), optionally (B) and optionally (D). It has beensurprisingly found that the extrusion of certain polymers (C),particular of high molecular weight polyethylene oxides, yieldsintermediates exhibiting some kind of memory effect: when the singulatedextrudates are shaped at ambient temperature, e.g. by press-forming,dosage forms are obtained which tend to regain their original outer formupon storage under stressed storage conditions, i.e. they return to theform they had prior to shaping.

The shape of the dosage form upon storage at stressed conditions, e.g.at 40° C./75% RH, may also be unstable for other reasons.

Said memory effect significantly deteriorates the storage stability ofthe dosage form, as by regaining its outer form several properties ofthe dosage form are changed. The same applies to any changes of theouter form due to other reasons.

It has been found that, for example, depending on the extrusionconditions a significant expansion of the strand may occur therebyresulting in an increase of the volume of the extrudate, i.e. a decreaseof its density. Said expansion may be compensated by subsequentlypress-forming the singulated extrudate at a sufficient pressure, sinceunder these conditions the expansion of the material may be reversed.

However, if press-forming has been performed at ambient temperature, thememory effect of the compressed extrudate will cause it to swell and toexpand upon storage, thereby significantly increasing the volume of thedosage form.

It has been surprisingly found that such memory effect may be suppressedif shaping of the singulated extrudate is performed at increasedtemperature, i.e. in the plasticized state of the mixture of components(A), (C), optionally (B) and optionally (D). Preferably, shaping isperformed at a pressure of at least 1 kN, more preferably within therange from 2 kN to 50 kN, e.g. by means of a tablet press. Preferably,shaping is performed at a temperature which preferably is about 40° C.,more preferably about 30° C. and in particular about 25° C. below themelting range of the mixture of components (A), (C), optionally (B) andoptionally (D). The melting range of a given mixture may be determinedby conventional methods, preferably by DSC (e.g. with a DSC model 2920(TA Instruments, New Castle) and ultrahigh pure nitrogen as purge gas ata flow rate of 150 ml./min; approximate sample weight of 10-20 mg,sealed in nonhermetic aluminium pans; temperature ramp speed 10°C./min).

In a preferred embodiment the outer shape of the dosage form accordingto the invention does not substantially change when being stored for atleast 12 h, preferably for at least 24 h, at 40° C. and 75% RH,preferably in an open container.

In a preferred embodiment the volume of the dosage form according to theinvention increases by not more than 20% or 17.5%, more preferably notmore than 15% or 12.5%, still more preferably not more than 10% or 7.5%,most preferably not more than 6.0%, 5.0% or 4.0% and in particular notmore than 3.0%, 2.0% or 1.0% when being stored for at least 12 h,preferably for at least 24 h, at a temperature of 20° C. below themelting range of the mixture of components (A), (C), optionally (B) andoptionally (D), optionally at a temperature of 40° C. and 75% RH.

In a further preferred embodiment, the dosage form according to theinvention assumes the form of a tablet, a capsule or is in the form ofan oral osmotic therapeutic system (OROS), preferably if at least onefurther abuse-preventing component (a)-(f) is also present.

If components (c) and/or (d) and/or (f) are present in the dosage formaccording to the invention, care must be taken to ensure that they areformulated in such a manner or are present in such a low dose that, whencorrectly administered, the dosage form is able to bring about virtuallyno effect which impairs the patient or the efficacy of the activeingredient.

If the dosage form according to the invention contains component (d)and/or (f), the dosage must be selected such that, when correctly orallyadministered, no negative effect is caused. If, however, the intendeddosage of the dosage form is exceeded in the event of abuse, nausea oran inclination to vomit or a bad flavor are produced. The particularquantity of component (d) and/or (f) which can still be tolerated by thepatient in the event of correct oral administration may be determined bythe person skilled in the art by simple preliminary testing.

If, however, irrespective of the fact that the dosage form according tothe invention is virtually impossible to pulverize, the dosage formcontaining the components (c) and/or (d) and/or (f) is provided withprotection, these components should preferably be used at a dosage whichis sufficiently high that, when abusively administered, they bring aboutan intense negative effect on the abuser. This is preferably achieved byspatial separation of at least the active ingredient or activeingredients from components (c) and/or (d) and/or (f), wherein theactive ingredient or active ingredients is/are present in at least onesubunit (X) and components (c) and/or (d) and/or (f) is/are present inat least one subunit (Y), and wherein, when the dosage form is correctlyadministered, components (c), (d) and (f) do not exert their effect ontaking and/or in the body and the remaining components of theformulation, in particular component (C) and optionally (D), areidentical.

If the dosage form according to the invention comprises at least 2 ofcomponents (c) and (d) or (f), these may each be present in the same ordifferent subunits (Y). Preferably, when present, all the components (c)and (d) and (f) are present in one and the same subunit (Y).

For the purposes of the present invention, subunits are solidformulations, which in each case, apart from conventional auxiliarysubstances known to the person skilled in the art, contain the activeingredient(s), at least one polymer (C) and the optionally presentcomponent (D) and optionally at least one of the optionally presentcomponents (a) and/or (b) and/or (e) or in each case at least onepolymer (C) and optionally (D) and the antagonist(s) and/or emetic(s)and/or component (e) and/or component (f) and optionally at least one ofthe optionally present components (a) and/or (b). Care must here betaken to ensure that each of the subunits is formulated in accordancewith the above-stated process.

One substantial advantage of the separated formulation of activeingredients from components (c) or (d) or (f) in subunits (X) and (Y) ofthe dosage form according to the invention is that, when correctlyadministered, components (c) and/or (d) and/or (f) are hardly releasedon taking and/or in the body or are released in such small quantitiesthat they exert no effect which impairs the patient or therapeuticsuccess or, on passing through the patient's body, they are onlyliberated in locations where they cannot be sufficiently absorbed to beeffective. When the dosage form is correctly administered, preferablyhardly any of components (c) and/or (d) and/or (f) is released into thepatient's body or they go unnoticed by the patient.

The person skilled in the art will understand that the above-statedconditions may vary as a function of the particular components (c), (d)and/or (f) used and of the formulation of the subunits or the dosageform. The optimum formulation for the particular dosage form may bedetermined by simple preliminary testing. What is vital is that eachsubunit contains the polymer (C) and optionally component (D) and hasbeen formulated in the above-stated manner.

Should, contrary to expectations, the abuser succeed in comminuting sucha dosage form according to the invention, which comprises components (c)and/or (e) and/or (d) and/or (f) in subunits (Y), for the purpose ofabusing the active ingredient and obtain a powder which is extractedwith a suitable extracting agent, not only the active ingredient butalso the particular component (c) and/or (e) and/or (f) and/or (d) willbe obtained in a form in which it cannot readily be separated from theactive ingredient, such that when the dosage form which has beentampered with is administered, in particular by oral and/or parenteraladministration, it will exert its effect on taking and/or in the bodycombined with an additional negative effect on the abuser correspondingto component (c) and/or (d) and/or (f) or, when the attempt is made toextract the active ingredient, the coloration will act as a deterrentand so prevent abuse of the dosage form.

A dosage form according to the invention, in which the active ingredientor active ingredients is/are spatially separated from components (c),(d) and/or (e), preferably by formulation in different subunits, may beformulated in many different ways, wherein the corresponding subunitsmay each be present in the dosage form according to the invention in anydesired spatial arrangement relative to one another, provided that theabove-stated conditions for the release of components (c) and/or (d) arefulfilled.

The person skilled in the art will understand that component(s) (a)and/or (b) which are optionally also present may preferably beformulated in the dosage form according to the invention both in theparticular subunits (X) and (Y) and in the form of independent subunitscorresponding to subunits (X) and (Y), provided that neither theabuse-proofing nor the active ingredient release in the event of correctadministration is impaired by the nature of the formulation and thepolymer (C) and optionally (D) is included in the formulation andformulation is carried out in accordance with the above-stated processin order to achieve the necessary hardness.

In a preferred embodiment of the dosage form according to the invention,subunits (X) and (Y) are present in multiparticulate form, whereinmicrotablets, microcapsules, micropellets, granules, spheroids, beads orpellets are preferred and the same form, i.e. shape, is selected forboth subunit (X) and subunit (Y), such that it is not possible toseparate subunits (X) from (Y) by mechanical selection. Themultiparticulate forms are preferably of a size in the range from 0.1 to3 mm, preferably of 0.5 to 2 mm.

The subunits (X) and (Y) in multiparticulate form may also preferably bepackaged in a capsule or be pressed into a tablet, wherein the finalformulation in each case proceeds in such a manner that the subunits (X)and (Y) are also retained in the resultant dosage form.

The multiparticulate subunits (X) and (Y) of identical shape should alsonot be visually distinguishable from one another so that the abusercannot separate them from one another by simple sorting. This may, forexample, be achieved by the application of identical coatings which,apart from this disguising function, may also incorporate furtherfunctions, such as, for example, controlled release of one or moreactive ingredients or provision of a finish resistant to gastric juiceson the particular subunits.

The multiparticulate subunits may also be formulated as an oral dosageform as a slurry or suspension in pharmaceutically safe suspendingmedia.

In a further preferred embodiment of the present invention, subunits (X)and (Y) are in each case arranged in layers relative to one another.

The layered subunits (X) and (Y) are preferably arranged for thispurpose vertically or horizontally relative to one another in the dosageform according to the invention, wherein in each case one or morelayered subunits (X) and one or more layered subunits (Y) may be presentin the dosage form, such that, apart from the preferred layer sequences(X)-(Y) or (X)-(Y)-(X), any desired other layer sequences may beconsidered, optionally in combination with layers containing components(a) and/or (b).

Another preferred dosage form according to the invention is one in whichsubunit (Y) forms a core which is completely enclosed by subunit (X),wherein a separation layer (z) may be present between said layers. Sucha structure is preferably also suitable for the above-statedmultiparticulate forms, wherein both subunits (X) and (Y) and anoptionally present separation layer (Z), which must satisfy the hardnessrequirement according to the invention, are formulated in one and thesame multiparticulate form. In a further preferred embodiment of thedosage form according to the invention, the subunit (X) forms a core,which is enclosed by subunit (Y), wherein the latter comprises at leastone channel which leads from the core to the surface of the dosage form.

The dosage form according to the invention may comprise, between onelayer of the subunit (X) and one layer of the subunit (Y), in each caseone or more, preferably one, optionally swellable separation layer (Z)which serves to separate subunit (X) spatially from (Y).

If the dosage form according to the invention comprises the layeredsubunits (X) and (Y) and an optionally present separation layer (Z) inan at least partially vertical or horizontal arrangement, the dosageform preferably takes the form of a tablet, a coextrudate or a laminate.

In one particularly preferred embodiment, the entirety of the freesurface of subunit (Y) and optionally at least part of the free surfaceof subunit(s) (X) and optionally at least part of the free surface ofthe optionally present separation layer(s) (Z) may be coated with atleast one barrier layer (Z′) which prevents release of component (c)and/or (e) and/or (d) and/or (f). The barrier layer (Z′) must alsofulfill the hardness conditions according to the invention.

Another particularly preferred embodiment of the dosage form accordingto the invention comprises a vertical or horizontal arrangement of thelayers of subunits (X) and (Y) and at least one push layer (p) arrangedtherebetween, and optionally a separation layer (z), in which dosageform the entirety of the free surface of layer structure consisting ofsubunits (X) and (Y), the push layer and the optionally presentseparation layer (Z) is provided with a semipermeable coating (E), whichis Permeable to a release medium, i.e. conventionally a physiologicalliquid, but substantially impermeable to the active ingredient and tocomponent (c) and/or (d). and/or (f), and wherein this coating (E)comprises at least one opening for release of the active ingredient inthe area of subunit (X).

A corresponding dosage form is known to the person skilled in the art,for example under the name oral osmotic therapeutic system (OROS), asare suitable materials and methods for the production thereof, interalia from U.S. Pat. Nos. 4,612,008, 4,765,989 and 4,783,337. Thedisclosure of these references is expressly incorporated herein and madea part of this present application.

In a further preferred embodiment, the subunit (X) of the dosage formaccording to the invention is in the form of a tablet, the edge face ofwhich and optionally one of the two main faces is covered with a barrierlayer (Z′) containing component (c) and/or (d) and/or (f).

The person skilled in the art will understand that the auxiliarysubstances of the subunit(s) (X) or (Y) and of the optionally presentseparation layer(s) (Z) and/or of the barrier layer(s) (Z′) used informulating the dosage form according to the invention will vary as afunction of the arrangement thereof in the dosage form according to theinvention, the mode of administration and as a function of theparticular active ingredient of the optionally present components (a)and/or (b) and/or (e) and of component (c) and/or (d) and/or (f). Thematerials which have the requisite properties are in each case known perse to the person skilled in the art.

If release of component (c) and/or (d) and/or (f) from subunit (Y) ofthe dosage form according to the invention is prevented with theassistance of a cover, preferably a barrier layer, the subunit mayconsist of conventional materials known to the person skilled in theart, providing that it contains at least one polymer (C) and optionally(D) to fulfill the hardness condition of the dosage form according tothe invention.

If a corresponding barrier layer (Z′) is not provided to prevent releaseof component (c) and/or (d) and/or (f), the materials of the subunitsshould be selected such that release of the particular component (c)and/or (d) from subunit (Y) is virtually ruled out. The materials whichare stated below to be suitable for production of the barrier layer maypreferably be used for this purpose.

Preferred materials are those which are selected from the groupcomprising alkylcelluloses, hydroxyalkyl-celluloses, glucans,scleroglucans, mannans, xanthans, copolymers ofpoly[bis(p-carboxyphenoxy)propane and sebacic acid, preferably in amolar ratio of 20:80 (commercially available under the name Polifeprosan20®), carboxymethyl celluloses, cellulose ethers, cellulose esters,nitrocelluloses, polymers based on (meth)acrylic acid and the estersthereof, polyamides, polycarbonates, polyalkylenes, polyalkyleneglycols, polyalkylene oxides, polyalkylene terephthalates, polyvinylalcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls,polyglycolides, polysiloxanes and polyurethanes and the copolymersthereof.

Particularly suitable materials may be selected from the groupcomprising methylcellulose, ethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, celluloseacetate, cellulose propionate (of low, medium or high molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, carboxymethylcellulose, cellulose triacetate, sodiumcellulose sulfate, polymethyl methacrylate, polyethyl methacrylate,polybutyl methacrylate, polyisobutyl methacrylate, polyhexylmethacrylate, polyisodecyl methacrylate, polylauryl methacrylate,polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate,polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene, low densitypolyethylene, high density polyethylene, polypropylene, polyethyleneglycol, polyethylene oxide, polyethylene terephthalate, polyvinylalcohol, polyvinyl isobutyl ether, polyvinyl acetate and polyvinylchloride.

Particularly suitable copolymers may be selected from the groupcomprising copolymers of butyl methacrylate and isobutyl methacrylate,copolymers of methyl vinyl ether and maleic acid with high molecularweight, copolymers of methyl vinyl ether and maleic acid monoethylester, copolymers of methyl vinyl ether and maleic anhydride andcopolymers of vinyl alcohol and vinyl acetate.

Further materials which are particularly suitable for formulating thebarrier layer are starch-filled polycaprolactone (WO98/20073), aliphaticpolyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1),aliphatic and aromatic polyester urethanes (DE 19822979),polyhydroxyalkanoates, in particular polyhydroxybutyrates,polyhydroxyvalerates, casein (DE 4 309 528), polylactides andcopolylactides (EP 0 980 894 A1). The disclosure of these references isexpressly incorporated herein and made a part of this presentapplication.

The above-stated materials nay optionally be blended with furtherconventional auxiliary substances known to the person skilled in theart, preferably selected from the group comprising glycerylmonostearate, semi-synthetic triglyceride derivatives, semi-syntheticglycerides, hydrogenated castor oil, glyceryl palmitostearate, glycerylbehenate, polyvinyl-pyrrolidone, gelatine, magnesium stearate, stearicacid, sodium stearate, talcum, sodium benzoate, boric acid and colloidalsilica, fatty acids, substituted triglycerides, glycerides,polyoxyalkylene glycols and the derivatives thereof.

If the dosage form according to the invention comprises a separationlayer (Z′), said layer, like the uncovered subunit (Y), may preferablyconsist of the above-stated materials described for the barrier layer.The person skilled in the art will understand that release of the activeingredient or of component (c) and/or (d) from the particular subunitmay be controlled by the thickness of the separation layer.

The dosage form according to the invention exhibits controlled releaseof the active ingredient. It is preferably for twice dailyadministration to patients.

The release properties of the dosage form according to the invention aresubstantially independent from the pH value of the release medium, i.e.preferably the release profile in artificial intestinal juicesubstantially corresponds to the release profile in artificial gastricjuice. Preferably, at any given time point the release profiles deviatefrom one another by not more than 20%, more preferably not more than15%, still more preferably not more than 10%, yet more preferably notmore than 7.5%, most preferably not more than 5.0% and in particular notmore than 2.5%.

Preferably, the dosage form according to the invention exhibits auniform release profile. Preferably, the release profile of the activesubstance with abuse potential (A) is inter-individually uniform (i.e.when comparing dosage forms obtained from the same process) and/oruniform within a single dosage form (i.e. when comparing segments of thesame dosage form). Preferably, when comparing two probes each having amass of preferably 500 mg, the total amount of the released activesubstance for any given time point of the measurement does not deviateby more than 20%, more preferably not more than 15%, still morepreferably not more than 10%, yet more preferably not more than 7.5%,most preferably not more than. 5.0% and in particular not more than2.5%.

Preferably, the release profile of the dosage form according to thepresent invention is stable upon storage, preferably upon storage atelevated temperature, e.g. 37° C., for 3 month in sealed containers. Inthis regard “stable” means that when comparing the initial releaseprofile with the release profile after storage, at any given time pointthe release profiles deviate from one another by not more than 20%, morepreferably not more than 15%, still more preferably not more than 10%,yet more preferably not more than 7.5%, most preferably not more than5.0% and in particular not more than 2.5%.

The dosage form according to the invention may comprise one or moreactive ingredients at least partially in controlled release form,wherein controlled release may be achieved with the assistance ofconventional materials and methods known to the person skilled in theart, for example by embedding the active ingredient in a controlledrelease matrix or by the application of one or more controlled releasecoatings. Active ingredient releaser must, however, be controlled suchthat the above-stated conditions are fulfilled in each case, for examplethat, in the event of correct administration of the dosage form, theactive ingredient or active ingredients are virtually completelyreleased before the optionally present component (c) and/or (d) canexert an impairing effect. Addition of materials effecting controlledrelease must moreover not impair the necessary hardness.

Controlled release from the dosage form according to the invention ispreferably achieved by embedding the active ingredient in a matrix. Theauxiliary substances acting as matrix materials control activeingredient release. Matrix materials may, for example, be hydrophilic,gel-forming materials, from which active ingredient release proceedsmainly by diffusion, or hydrophobic materials, from which activeingredient release proceeds mainly by diffusion from the pores in thematrix.

Physiologically acceptable, hydrophobic materials which are known to theperson skilled in the art may be used as matrix materials. Polymers,particularly preferably cellulose ethers, cellulose esters and/oracrylic resins are preferably used as hydrophilic matrix materials.Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivativesthereof, such as the salts, amides or esters thereof are veryparticularly preferably used as matrix materials.

Matrix materials prepared from hydrophobic materials, such ashydrophobic polymers, waxes, fats, long chain fatty acids, fattyalcohols or corresponding esters or ethers or mixtures thereof are alsopreferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30fatty alcohols and/or waxes or mixtures thereof are particularlypreferably used as hydrophobic materials.

It is also possible to use mixtures of the above-stated hydrophilic andhydrophobic materials as matrix materials.

Component (C) and the optionally present component (D), which serve toachieve the breaking strength of at least 500 N which is necessaryaccording to the invention may furthermore also optionally serve asadditional matrix materials.

If the dosage form according to the invention is intended for oraladministration, it may also preferably comprise a coating which isresistant to gastric juices and dissolves as a function of the pH valueof the release environment. By means of this coating, it is possible toensure that the dosage form according to the invention passes throughthe stomach undissolved and the active ingredient is only released inthe intestines. The coating which is resistant to gastric juicespreferably dissolves at a pH value of between 5 and 7.5.

Corresponding materials and methods for the controlled release of activeingredients and for the application of coatings which are resistant togastric juices are known to the person skilled in the art, for examplefrom “Coated Pharmaceutical Dosage Forms Fundamentals, ManufacturingTechniques, Biopharmaceutical Aspects, Test Methods and Raw Materials”by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart,1st edition, 1998, Medpharm Scientific Publishers. The disclosure ofthese references is expressly incorporated herein and made a part ofthis present application.

Method for Determining the Breaking Strength

In order to verify whether a polymer may be used as component (C) or(D), the polymer is pressed to form a tablet with a diameter of 10 mmand a height of 5 mm using a force of 150 N at a temperature which atleast corresponds to the softening point of the polymer and isdetermined with the assistance of a DSC diagram of the polymer. Usingtablets produced in this manner, breaking strength is determined withthe apparatus described below in accordance with the method fordetermining the breaking strength of tablets published in the EuropeanPharmacopoeia 1997, page 143-144, method no. 2.9.8. The apparatus usedfor the measurement is a “Zwick Z 2.5” materials tester, Fmax=2.5 kNwith a maximum draw of 1150 mm, which should be set up with 1 column and1 spindle, a clearance behind of 100 mm and a test speed adjustablebetween 0.1 and 800 mm/min together with testControl software.Measurement is performed using a pressure piston with screw-in insertsand a cylinder (diam. 10 mm), a force transducer, Fmax. 1 kN, diameter=8mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, withmanufacturer's test certificate M to DIN 55350-18 (Zwick gross forceFmax=1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany)with order no. BTC-FR 2.5 TH. D09 for the tester, order no. BTC-LC0050N. P01 for the force transducer, order no. BO 70000 S06 for thecentering device.

FIG. 3 shows the measurement of the breaking strength of a tablet, inparticular the tablet (4) adjustment device (6) used for this purposebefore and during the measurement. To this end, the tablet (4) is heldbetween the upper pressure plate (1) and the lower pressure plate (3) ofthe force application apparatus (not shown) with the assistance of two2-part clamping devices, which are in each case firmly fastened (notshown) with the upper and lower pressure plate once the spacing (5)necessary for accommodating and centring the tablet to be measured hasbeen established. The spacing (5) may be established by moving the2-part clamping devices horizontally outwards or inwards in each case onthe pressure plate on which they are mounted.

The tablets deemed to be resistant to breaking under a specific loadinclude not only those which have not broken but also those which mayhave suffered plastic deformation under the action of the force.

In the case of the dosage forms according to the invention, breakingstrength is determined in accordance with the stated method, dosageforms other than tablets also being tested.

The following Examples illustrate the invention purely by way of exampleand without restricting the general concept of the invention.

Example 1

Components Per tablet Per batch Tramadol HCl 100.0 mg 1495.0 gPolyethylene oxide, NF, 167.8 mg 2508.6 g MW 7 000 000 (Polyox WSR 303,Dow Chemicals) Hydroxypropylmethylcellulose  33.5 mg  500.8 g 100 000mPa-s Polyethylene glycol (PEG 6000)  33.5 mg  500.8 gButylhydroxytoluene (BHT)  0.2 mg   3.0 g Total weight 335.0 mg 5008.2 g

The stated quantity of BHT was dissolved in ethanol (96%), such that a7.7% (mass/mass) ethanolic solution was obtained. This was mixedinitially with 150 g of polyethylene oxide in a high speed mixer for 30minutes and then the remaining quantity of polyethylene oxide was addedand stirring continued for a further 30 minutes. The composition wasdried for 12 h at 40° C. All the further components were added and mixedfor 15 min in a free-fall mixer. The powder mixture was apportioned intoan extruder. Extrusion was performed using a model Micro 27 GL 40 Ddouble screw extruder with a spindle diameter of 18 mm manufactured byLeistritz (Niirnberg). Screws with blunt ends were used, the hex socketat the end of the screws being closed with a cap. The die used is aheatable round die with a diameter of 8 mm. The entire process wasperformed under an N₂ atmosphere.

The following parameters were selected for extrusion:

Screw speed: 100 rpmThroughput: 4 kg/hProduct temperature: 125° C.Casing temperature: 120° C.

The extrudate, which was still hot, was cooled under a nitrogenatmosphere. The cooled strand was singulated into biplanar tablets. Thetablets did not break when exposed to a force of 500 N. The tabletscould not be comminuted either with a hammer or with the assistance of amortar and pestle.

The color of the cooled strand or of the 10 tablets singulated therefromwas determined at N 9.5/using the Munsell Book of Color, such that thedosage form produced by the process according to the invention did notexhibit any discoloration due to the thermoforming with the assistanceof an extruder.

Example 2

Components Per Tablet Per batch Oxycodon HC1 20.0 mg   410.1 g 13.7%Polyethylene oxide 7 000 000(Polyox 107.2 mg  2199.3 g 73.2% WSR 303,DOW Chemicals) Polyethylene glycol (PEG 6000) 15.0 mg   307.8 g 10.3%Hypromellose (Metholose 90 SH 3.8 mg  76.8 g  2.6% 100 000 cP, ShinEtsu)α-Tocopherol 0.2 mg   3.0 g  0.1% Aerosil (highly disperse Si0₂) 0.2 mg  3.0 g  0.1% 146.4 mg  3000.0 g  100%

50 g of the polyethylene oxide, 3 g ca-tocopherol and 3 g Aerosil weremixed to a homogeneous mixture by means of a mortar. All the furthercomponents were added and mixed for 15 minutes in a free-fall mixer.

Extrusion was performed using a model Micro 27 PH 40 D twin screwextruder manufactured by Leistritz Niirnberg). Screws having eccentricends were used. The die used is a heatable round die having a diameterof 9 mm.

The following parameters were selected for extrusion:

-   -   Screw speed: 100 rpm    -   Throughput: 4 kg/h    -   Product temperature: 134° C.    -   Casing temperature: heating zones 1 to 10: 100° C.        -   heating zone 11 (die): 120° C.

The extrudate, which was still hot, was cooled. No nitrogen atmospherewas used. The product did not exhibit any yellowish discoloration.

The cooled strand was singulated into biplanar slices. The finalpress-forming was performed by means on an eccentric tablet press (modelEKO). Oblong punches (width 5 mm, length 12 mm) were used as tablettingtool. The respective tablets (mass and form) were punched from theslices and press-formed. One tablet was obtained from one slice.

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus with sinker in accordance withPharm. Eur. The temperature of the release medium was 37° C. and therotational speed of the stirrer 75 min⁻¹. 600 ml of artificialintestinal juice, pH 6.8 were used as release medium. The releasedquantity of active ingredient present in the dissolution medium at eachpoint in time was determined by spectrophotometry.

Time Amount Released  60 min 36% 240 min 79% 480 min 99% 720 min 107%

Example 3

Per Per Components Table Batch % Oxycodon HC1 20.0 mg 333.3 g 11.1Polyethylene oxide 7 000 000 122.6 mg  2060.7 g  68.7 (Polyox WSR 303,DOW Chemicals) Polyethylene glycol (PEG 6000) 18.0 mg 300.0 g 10.0Hypromellose (Metholose 90 SH 18.0 mg 300.0 g 10.0 100 000 cP, ShinEtsu)α-Tocopherol  0.2 mg  3.0 g 0.1 Aerosil (highly disperse SiO₂)  0.2 mg 3.0 g 0.1  180 mg 3000.0 g  100%

50 g of the polyethylene oxide, 3 g α-todopherol and 3 g Aerosil weremixed to a homogeneous mixture by means of a mortar. All the furthercomponents were added and mixed for 15 minutes in free-fall mixer.

Extrusion was performed using a model Micro 27 PH 40 D twin screwextruder manufactured by Leistritz (Niirnberg). Screws having eccentricends were used. The die used is a heatable round die having a diameterof 9 mm.

The following parameters were selected for extrusion:

-   -   Screw speed: 100 rpm    -   Throughput: 4 kg/h    -   Product temperature: 134° C.    -   Casing temperature: heating zones 1 to 10: 100° C.        -   heating zone 11 (die): 120° C.

The extrudate, which was still hot, was cooled. No nitrogen atmospherewas used. The product did not exhibit any yellowish discoloration.

The cooled strand was singulated into biplanar slices. The finalpress-forming was performed by means on an eccentric tablet press (modelEKO). Oblong punches (width 5 mm, length 12 mm) were used as tablettingtool. The respective tablets (mass and form) were punched from theslices and press-formed. One tablet was obtained from one slice.

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus with sinker in accordance withPharm. Eur. The temperature of the release medium was 37° C. and therotational speed of the stirrer 75 min-1. 600 ml of artificialintestinal juice, pH 6.8 were used as release medium. The releasedquantity of active ingredient present in the dissolution medium at eachpoint in time was determined by spectrophotometry.

Amount Time released  60 min 33% 240 min 76% 480 min 100% 720 min 108%

Example 4

Per Per Components Table Batch % Tramadol 116.5 mg 349.0 g 34.9Polyethylene oxide 7 000 000 150.2 mg 450.0 g 45.0 (Polyox WSR 303, DOWChemicals) Polyethylene glycol (PEG 6000)  33.4 mg 100.0 g 10.0Hypromellose (Metholose 90 SH  33.4 mg 100.0 g 10.0 100 000 cP,ShinEtsu) Butylhydroxytoluene  0.3 mg  1.0 g 0.1 333.8 mg  1000 g 100%

45 g of the polyethylene oxide and 1 g butylhydroxytoluene were mixed toa homogeneous mixture by means of a mortar. All the further componentswere added and mixed for 15 minutes in a free-fall mixer.

Extrusion was performed using a model Micro 27 PH 40 D twin screwextruder manufactured by Leistritz (Niirnberg). Screws having eccentricends were used. The die used is a heatable round die having a diameterof 9 mm.

The following parameters were selected for extrusion:

-   -   Screw speed: 100 rpm    -   Throughput: 4 kg/h.    -   Product temperature: 134° C.    -   Casing temperature: heating zones 1 to 10: 100° C.        -   heating zone 11 (die): 120° C.

The extrudate, which was still hot, was cooled. No nitrogen atmospherewas used. The product did not exhibit any yellowish discoloration.

The cooled strand was singulated into biplanar slices. The finalpress-forming was performed by means on an eccentric tablet press (modelEKO). Round punches (diameter 10 mm) having a radius of curvature of 8mm were used as tabletting tool. One tablet was obtained from one slice.

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

Example 5

Per Per Components Table Batch % Oxycodon HCl 40.00 mg 133.3 g 13.3Polyethylene oxide 5 000 000 190.0 mg 643.3 g 63.3 (Polyox WSRCoagulant, DOW Chemicals) Polyethylene glycol (PEG 6000)  30.0 mg 100.0g 10.0 Hypromellose (Metholose 90 SH  30.0 mg 100.0 g 10.0 100 000 cP,ShinEtsu) α-Tocopherol  5.0 mg  16.7 g 1.7 Aerosil (highly disperseSiO₂)  5.0 mg  16.7 g 1.7  300 mg  1000 g 100

50 g of the polyethylene oxide, 5 g a-tocopherol and 5 g Aerosil weremixed to a homogeneous mixture by means of a mortar. All the furthercomponents were added and mixed for 15 minutes in a free-fall mixer.

Extrusion was performed using a model Micro 27 PH 40 D twin screwextruder manufactured by Leistritz (Nernberg). Screws having eccentricends were used. The die used is a heatable round die having a diameterof 9 mm.

The following parameters were selected for extrusion:

-   -   Screw speed; 100 rpm    -   Throughput: 4 kg/h    -   Product temperature: 134° C.    -   Casing temperature: heating zones 1 to 10: 100° C.        -   heating zone 11 (die): 120° C.

The extrudate, which was still hot, was cooled. No nitrogen atmospherewas used. The product exhibited a slight yellowish coloration. However,this coloration was merely caused by the natural color of ca-tocopherol,but was not intensified by the extrusion, i.e. the extrusion wasperformed without discoloration.

The cooled strand was singulated into biplanar slices. The finalpress-forming was performed by means on an eccentric tablet press (modelEKO). Round punches (diameter 10 mm) having a radius of curvature of 8mm were used as tabletting tool. One tablet was obtained from one slice.

The breaking strength of the tablets was determined with the statedapparatus in accordance with the stated method. The tablets did notcrush when exposed to a force of 500 N. The tablet could not becomminuted with a hammer. This could not be achieved with the assistanceof a pestle and mortar either.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus with sinker in accordance withPharm. Eur. The temperature of the release medium was 37° C. and therotational speed of the stirrer 75 min⁻¹. 600 ml of artificialintestinal juice, pH 6.8 were used as release medium. The releasedquantity of active ingredient present in the dissolution medium at eachpoint in time was determined by spectrophotometry.

Amount Time released  60 min 33% 240 min 76% 480 min 100% 720 min 108%

1. An abuse-proofed dosage form thermoformed by extrusion withoutdiscoloration comprising one or more active ingredients with abusepotential (A), optionally physiologically acceptable auxiliarysubstances (B), at least one synthetic or natural polymer (C) andoptionally at least one wax (D), wherein the dosage form exhibits abreaking strength of at least 500 N.
 2. The dosage form according toclaim 1, which in the form of a tablet.
 3. The dosage form according toclaim 1, which contains as polymer (C) at least one polymer selectedfrom the group consisting of polyalkylene-oxide, polyethylene,polypropylene, polyvinyl chloride, polycarbonate, polystyrene,polyacrylate, copolymers thereof and mixtures thereof.
 4. The dosageform according to claim 3, wherein the polyalkylene oxide is selectedfrom the group consisting of polymethylene oxide, polyethylene oxide,polypropylene oxide, copolymers thereof and mixtures thereof.
 5. Thedosage form according to claim 1, wherein the polymer (C) comprisespolyethylene oxide having a molecular weight of at least 0.5 million. 6.The dosage form according to claim 5, wherein the molecular weight ofthe polyethylene oxide (C) is at least 1 million.
 7. The dosage formaccording to claim 6, wherein the molecular weight of the polyethylene.oxide is in the range of from about 1 to about 15 million.
 8. The dosageform according to claim 1, which contains the wax (D), and the wax (D)is at least one natural, semi-synthetic or synthetic wax with asoftening point of at least 60° C.
 9. The dosage form according to claim8, wherein the wax (D) is carnauba wax or beeswax.
 10. The dosage formaccording to claim 1, wherein the active ingredient (A) is at least oneactive ingredient selected from the group consisting of opioids,tranquilizers, stimulants, barbiturates and further narcotics.
 11. Thedosage form according to claim 1, which additionally comprises (a) atleast one substance which irritates the nasal passages and/or pharynx;and/or (b) at least one viscosity-increasing agent, which in thepresence of an active ingredient extracted from the dosage form using aliquid medium, forms a gel with the extract obtained from the dosageform, which gel optionally remains visually distinguishable whenintroduced into a further quantity of an aqueous liquid; and/or (c) atleast one antagonist for the active ingredient or active ingredientswith abuse potential; and/or (d) at least one emetic; and/or (e) atleast one dye; and/or (f) at least one bitter substance.
 12. The dosageform according to claim 11, which comprises component (b), whereincomponent (b) is at least one viscosity-increasing agent selected fromthe group consisting of microcrystalline cellulose combined withcarboxymethylcellulose sodium, polyacrylic acid, locust bean flour,pectins, waxy maize starch, sodium alginate, guar flour, iota carrageen,karaya gum, gellan gum, galactomannan, tara bean flour, propylene glycolalginate, apple pectin, sodium hyaluronate; tragacanth, tara gum,fermeted polysaccharide welan gum, and xanthan gum.
 13. The dosage formaccording to claim 11, which comprises component (c), wherein component(c) is at least one opioid antagonist selected from the group consistingof naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine,naluphine and a corresponding physiologically acceptable compound, abase, and a salt thereof.
 14. The dosage forth according to claim 1,which contains at least one active ingredient with abuse potential (A)at least partially in controlled release form.
 15. The dosage formaccording to claim 14, wherein each of the active ingredients with abusepotential (A) is present in a controlled release matrix.
 16. The dosageform according to claim 15, wherein the controlled release matrixmaterial, comprises component (C) and/or the optionally presentcomponent (D).
 17. The dosage form according to claim 1, which comprisesa core and a tubular domain surrounding the core, wherein said tubulardomain has a morphology different from that of the core.
 18. The dosageform according to claim 17, wherein the core and the tubular domain havesubstantially the same chemical composition.
 19. The dosage formaccording to claim 17, wherein the tubular domain does not completelycover the core.
 20. The dosage form according to claim 1, whichcomprises a physiologically acceptable auxiliary substance (B), whereinthe physiologically acceptable auxiliary substance (B) is anantioxidant.
 21. The dosage form according to claim 20, wherein theantioxidant is selected from the group consisting of ascorbic acid,salts of ascorbic acid, butylhydroxyanisole, butylhydroxytoluene,monothioglycerol, phosphorous acid, vitamin C, vitamin E and thederivatives thereof, sodium bisulfite and <-tocopherol.
 22. A processfor the production of a dosage: form according to claim 1, comprising I)mixing components (A), the optionally present component (B), (C) and theoptionally present component (D) and co-mixing or separately mixing theoptionally present components (a) to (f) with the addition of component(C) and optionally (D) to form a resultant mixture or plurality ofresultant mixtures; II) heating the resultant mixture or the resultantmixtures in an extruder at least up to the softening point of component(C) and extruding the mixture as a plastic extrudate through an outletorifice of the extruder by application of force; and III) singulatingand forming the still plastic extrudate into the dosage form; or IV)cooling and forming the optionally reheated singulated extrudate intothe dosage form.
 23. The process according to claim 22, wherein processstep II) is performed by means of a twin-screw-extruder.
 24. The processaccording to claim 22, wherein process steps II) and III) and optionallyprocess steps I) and IV) are performed under an inert gas atmosphere.25. The process according to claim 24, wherein the inert gas atmosphereis nitrogen.
 26. The process according to claim 22, wherein mixing ofthe components according to process step I) proceeds in the extruderunder an inert gas atmosphere.
 27. The process according to claim 22,wherein the mixtures according to process step I) are co-extruded orseparately extruded.
 28. The process according to claim 22, wherein themixture or the mixtures according to process step 1) are extrudedthrough a die with at least one bore.
 29. The process according to claim22, wherein the extrudate is singulated by cutting.
 30. The processaccording to claim 22, wherein the extrudate is in the form of a strandand is shaped and singulated with the assistance of counter rotatingcalender rolls comprising opposing recesses in their outer sleeve. 31.The process according to claim 22, wherein the singulated extrudate ispelletized or pressed into tablets.
 32. The process according to claim22, wherein Swelling and expansion of the dosage form upon storage issuppressed by press forming the singulated extrudate at a pressure of atleast 1 kN and a temperature of between 25° C. and 40° C. below themelting range of the mixture of the components.
 33. The dosage formaccording to claim 1, wherein the one or more ingredients with abusepotential (A) are selected from the group consisting of oxycodone,oxymorphone, tapentadol, morphine and the physiologically acceptablesalts thereof.
 34. The dosage form according to claim 1, wherein thecontent of polymer (C) is at least 30 wt. % relative to the total weightof the dosage form.
 35. A dosage form obtainable by the processaccording to claim
 22. 36. A method of reducing the incidence of drugabuse of an active ingredient (A) with abuse potential, said methodcomprising providing said active ingredient (A) in the form of a dosageform according to claim 1.